AARS2 encodes the mitochondrial alanyl-tRNA synthetase responsible for charging tRNA(Ala) with alanine in mitochondria, essential for mitochondrial protein synthesis 1. Beyond its canonical aminoacylation function, AARS2 serves as an intracellular lactate sensor with micromolar affinity for L-lactate 2. In the presence of elevated lactate levels, AARS2 functions as a lactyltransferase, catalyzing ATP-dependent lysine lactylation of target proteins including cGAS and CPT2 23. This lactylation activity regulates multiple cellular processes: it inactivates cGAS by preventing liquid-like droplet formation necessary for DNA sensing, thereby inhibiting cGAS/STING signaling 2, and promotes follicle development through CPT2 inactivation and metabolic reprogramming 3. Pathogenic AARS2 mutations cause severe mitochondrial disorders including combined oxidative phosphorylation deficiency and progressive leukoencephalopathy with ovarian failure 45. Some POI-associated mutations exhibit gain-of-function lactyltransferase activity, leading to premature ovarian insufficiency through accelerated follicle depletion 3. AARS2 deficiency has also been implicated in severe childhood cardiomyopathies, highlighting its critical role in mitochondrial function across multiple organ systems 6.